Sofosbuvir, referred to herein as compound 1, L-alanine, N—[[P(S),2′R]-2′-deoxy-2′-fluoro-2′-methyl-P-phenyl-5′-uridylyl]-, 1-methylethyl ester, or (2S)-isopropyl 2-(((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate, having the following formula,
is an orally available, second generation uridine nucleoside analogue which inhibits the NS-5 protein of hepatitis C virus (HCV). Sofosbuvir and its isomer act as prodrugs and are converted through a series of in vivo transformations to an active triphosphate metabolite.
Sofosbuvir is described in U.S. Pat. No. 7,964,580. Processes for preparation of sofosbuvir and/or the phosphoramidate intermediates are described in WO 2008/121634, WO 2010/135569, WO 2011/123645, WO 2011/123668, WO 2012/012465 and WO 2002/057425. WO 2008/121634 describes a process for preparing sofosbuvir by coupling a substituted phosphochloridate compound with the nucleoside analogue, 2′-deoxy-2′-fluoro-2′-C-methyluridine. In this process the product is obtained as mixture of diastereomers (comprising sofosbuvir and the corresponding Rp isomer) which are separated using chiral chromatography. The other publications disclose other processes, some of which comprise coupling a single diastereomer of the phosphoramidate intermediate with the nucleoside analogue to afford sofosbuvir.
WO2010/135569 and WO 2012/012465 specifically disclose use of isopropyl ((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate and isopropyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate for the preparation of sofosbuvir by coupling with the nucleoside analog. Use of the above mentioned phosphoramidate intermediates in the coupling reaction has several drawbacks. Use of isopropyl ((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alaninate poses a safety concern and use of isopropyl ((S)-(perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate requires its preparation from the expensive raw material pentafluorophenol.
Other processes for preparing phosphoramidate derivatives are disclosed in IN 1446/MU/2014, WO 2014/008236, WO 2015/097605, WO 2012/012465, WO 2015/158317, WO 2016/016447 and WO 2016/016865
Prior art processes typically involve the preparation of single diastereomers of the phosphoramidate, achieved by either Dynamic Kinetic Resolution for converting the undesired diastereomer to the desired diastereomer, or use of preferential crystallization for isolation of one of the diastereomers. While the former has several advantages in terms of yield, to date it was realized for only a few phosphoramidates, whereas the latter requires additional processing steps. Further, the reactions typically employ toxic or costly reagents and are not suitable for industrial scale.
Therefore, there is a need in the art for improved processes for synthesizing Sofosbuvir with high yields, chemical purity and optical purity, which are suitable for industrial use.